A de novo purine synthesis intermediate activates pyruvate kinase M2 upon glucose starvation.
Major finding: A de novo purine synthesis intermediate activates pyruvate kinase M2 upon glucose starvation.
Mechanism: SAICAR accumulation increases glucose uptake, lactate production, and cellular energy levels.
Impact: SAICAR may regulate the balance between biosynthesis and energy production in cancer cells.
Tumor-specific expression of pyruvate kinase isoform M2 (PKM2) contributes to metabolic reprogramming necessary for survival in nutrient-limited conditions. The reduced pyruvate kinase activity of PKM2 relative to the M1 isoform predominantly expressed in normal cells likely results in the diversion of glycolytic intermediates to biosynthetic pathways to meet the demands of rapidly proliferating cancer cells, but the simultaneous requirement for pyruvate kinase activity for cancer cell survival indicates that PKM2 must balance cell growth and energy generation. Hypothesizing that allosteric regulators of PKM2 modulate this balance, Keller and colleagues extracted metabolites from cancer cells grown in high- or no-glucose medium and identified those capable of binding to PKM2 with liquid-chromatography mass spectrometry. Succinylaminoimidazolecarboxamide ribose-5′-phosphate (SAICAR), an intermediate of the de novo purine biosynthesis pathway, was identified in glucose-limiting conditions and was the only metabolite that specifically bound PKM2 among pyruvate kinases. SAICAR elevation was observed in all cancer cell lines upon glucose starvation but was undetectable in normal epithelial cells or fibroblasts. SAICAR binding increased the pyruvate kinase activity of PKM2 to a level near that of PKM1, and its accumulation was associated with increased glucose uptake, pyruvate levels, lactate fermentation, and cellular ATP levels in cancer cells. Under glucose-limiting conditions, higher SAICAR levels promoted cell survival, and this effect was dependent on the interaction of SAICAR with PKM2. Because SAICAR is an intermediate of nucleotide synthesis, which requires glycolytic intermediates, these findings suggest that SAICAR levels convey information on the cellular metabolic state to PKM2 and maintain an optimal balance between biosynthesis and pyruvate kinase–dependent energy production to promote the survival of cancer cells.